Abstract
BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF) is characterized by catastrophic loss of liver function in patients with advanced chronic liver disease, with 28-day mortality rates reaching up to 80%. Despite advances in intensive care, the high mortality primarily stems from the absence of a therapeutic modality that simultaneously addresses both the profound systemic inflammatory response and severe hepatic synthetic dysfunction. METHODS: We designed an integrated extracorporeal circuit, termed the UTOpiA system, which combines granulocyte and monocyte apheresis (GMA) with human induced pluripotent stem cell-derived hepatocyte-like cell (iHLC) organoids engineered with HLA-A, HLA-B, and CIITA triple knockout. The efficacy of UTOpiA was tested after direct whole blood exposure through venous flow in rat models of ACLF and acute liver failure (ALF). RESULTS: UTOpiA treatment significantly improved survival in both ACLF and ALF rat models, outperforming GMA or iHLC monotherapy and HepG2 cell-based devices. Improved survival was associated with reduced coma severity, improved liver biochemistry, and reduced hyperammonaemia, hyperbilirubinemia, and systemic inflammation. Transcriptomic and histological analyses revealed restoration of hepatic metabolic gene expression and hepatocyte regeneration. Mechanistically, iHLC-secreted α-fetoprotein suppressed hepatocyte cell cycle arrest via p21 downregulation and enhanced regeneration, while UTOpiA restored HNF4α activity and dampened pro-inflammatory cytokines, including IL-6 and TNF-α. CONCLUSIONS: The tandem UTOpiA circuit confers a significant survival benefit in preclinical rodent models of ACLF and ALF by providing anti-inflammatory, synthetic, and metabolic support. Elucidating the regenerative signals that promote recovery of the injured liver may further expand the potential of this whole blood extracorporeal system as a novel, off-the-shelf liver support therapy. IMPACT AND IMPLICATIONS: Restoring hepatic metabolism while controlling inflammation in acutely decompensated cirrhosis remains a major unmet clinical need. By combining HLA-modified human induced pluripotent stem cell-derived liver organoids with granulocyte and monocyte apheresis, we developed a bioartificial liver system that manages inflammation, restores liver function, and promotes regeneration in two rat models of severe liver failure. This therapy could offer an off-the-shelf treatment option for patients with life-threatening liver failure.